REVIEW published: 03 December 2019 doi: 10.3389/fmed.2019.00261
Status of Recombinant Factor VIII Concentrate Treatment for Hemophilia A in Italy: Characteristics and Clinical Benefits
Mario Schiavoni 1*, Mariasanta Napolitano 2, Gaetano Giuffrida 3, Antonella Coluccia 4, Sergio Siragusa 5, Valeria Calafiore 3, Giuseppe Lassandro 6 and Paola Giordano 6
1 Associazione per la Lotta alle Malattie Emorragiche e Trombotiche, Maglie, Italy, 2 Internal Medicine and Medical Specialities, Haematology Unit, Department of Health Promotion, Mother and Child Care, Reference Regional Center for Thrombosis and Haemostasis, University of Palermo, Palermo, Italy, 3 U.O.C. di Ematologia, A.O.U. Policlinico “Vittorio Emanuele”, Catania, Italy, 4 U.O.C di Medicina Interna, Centro Emofilia e Coagulopatie Rare-Ospedale “I.Veris delli Ponti”, Scorrano-ASL, Lecce, Italy, 5 U.O.C. di Ematologia, Università degli Studi, Palermo, Italy, 6 Dipartimento di Scienza Biomedica e Oncologia Umana, Università degli Studi di Bari “Aldo Moro”, Bari, Italy
The current interest in recombinant factor VIII (rFVIII) products stems from the fact that they offer a technological solution to prolonging the half-life of and reducing the risk of formation of alloantibodies (inhibitors) against FVIII in treated patients with hemophilia A (HA). The Italian health care system has authorized the use of a wide range of rFVIII concentrates of the first, second, and third generation, as well as new innovative rFVIII preparates with an extended half-life (EHL) (Kogenate FS®-Bayer, belonging to the Edited by: Marvin T. Nieman, second generation and replaced since 2017 by a product consisting of the same modified Case Western Reserve University, molecule; because it is only available until the end of the current year, it will not be United States considered in this review). Some of these products have unique pharmacodynamic and Reviewed by: pharmacokinetic (PK) profiles, including an EHL. The first-generation full-length rFVIII (FL- Thierry Burnouf, ® Taipei Medical University, Taiwan rFVIII), octocog alfa (Recombinate Baxter/BIOVIIIx), although the oldest rFVIII product, Wei Li, has several desirable features. Third-generation products include two modified octocog Marshall University, United States alfa molecules (Advate®, Shire; Kovaltry®, Bayer) as well as the B domain-deleted *Correspondence: ® Mario Schiavoni rFVIII (BDD-rFVIII) moroctocog alfa (ReFacto -Pfizer). The B domain-truncated (BDT- [email protected] rFVIII) turoctocog alfa (NovoEight®, Novo Nordisk), the BDD-rFVIII simoctocog alfa (Nuwiq®, Kedrion), the single-chain BDT-rVIII lonoctocog alfa (Afstyla®, CSL Behring), Specialty section: ® This article was submitted to and the BDD-rFVIIIFc efmoroctocog alfa (Elocta , Sobi-Biogen) are new, innovative Hematology, products. Simoctocog alfa, because its peculiarities, is considered a fourth-generation a section of the journal rFVIII concentrate. Turoctocog alfa, simoctocog alfa, and lonoctocog alfa have a high Frontiers in Medicine affinity for von Willebrand factor (vWF) that reduces renal clearance and prolongs the Received: 11 July 2019 Accepted: 28 October 2019 half-life of rFVIII. Efmoroctocog alfa, a first-in-class rFVIII-Fc fusion protein (rFVIIIFc), has Published: 03 December 2019 a half-life 1.5–1.8 times longer than that of conventional plasma-derived FVIII (pd-rFVIII) Citation: and other rFVIII products. Clinical studies have evaluated the efficacy, safety, and inhibitor Schiavoni M, Napolitano M, Giuffrida G, Coluccia A, Siragusa S, development of all these innovative concentrates in both previously treated (PTPs) and Calafiore V, Lassandro G and untreated patients (PUPs). This review considers the rFVIII products that are indicated Giordano P (2019) Status of for the treatment of patients with severe HA, focusing on those that are commercially Recombinant Factor VIII Concentrate Treatment for Hemophilia A in Italy: available in Italy. Their PK characteristics, immunogenicity, and clinical benefits are Characteristics and Clinical Benefits. discussed and compared. Front. Med. 6:261. doi: 10.3389/fmed.2019.00261 Keywords: Hemophilia A, recombinant Factor VIII products, pharmacokinetics, inhibitors, EHL-rFVIII
Frontiers in Medicine | www.frontiersin.org 1 December 2019 | Volume 6 | Article 261 Schiavoni et al. Recombinant Factor VIII in Italy
INTRODUCTION First-Generation Product Recombinate® The treatment of HA has dramatically improved since Recombinate R (octocog alfa, Baxter Biotech; distributed in Italy the 1990s, when the outbreak of blood-borne infections, by BIOVIIIx) is the only one of two first-generation rFVIII mainly due to the human immunodeficiency and hepatitis concentrates that is still commercially available in Italy. It is viruses, caused high rates of death and co-morbidities derived from a conditioned medium of chinese hamster ovary in many patients (1). This worldwide situation led (CHO) cell cultures transfected with cDNAs for FVIII (8–10). to the implementation of virus inactivation in the Human albumin, polyethylene glycol (PEG) 3350 (3 mg/ml), manufacture of pd-FVIII and rFVIII products, improving sodium chloride, calcium chloride, and histidine are added as replacement therapy. stabilizers. The product currently used in Italy is manufactured in In addition, many HA patients develop inhibitors Belgium and does not contain polysorbate 80. The co-expression in response to FVIII injections. Thus, since 2008, of recombinant vWF with rFVIII contributes to the stabilization the European Haemophilia Safety Surveillance System of the product. (EUHASS; www.EUHASS.org) has carried out safety Beginning in 1990, a multicenter, multinational, prospective monitoring of substitution therapies for patients with clinical trial of Recombinate R was conducted on PUPs with hemophilia (2). severe/moderate HA (baseline FVIII ≤2%) in order to evaluate All rFVIII products have an improved safety profile, as the safety and efficacy of the product, including the development their production includes virus inactivation procedures similar of inhibitors (11). Of the 79 PUPs enrolled, 76 received at least to those used in pd-FVIII concentrates (in first-generation one infusion of the concentrate, and the 72 patients (91%) who ◦ products, human albumin underwent pasteurization at 60 C continued in the study were tested for rFVIII inhibitors. Adverse for 10 h; a solvent/detergent (S/D) step and nanofiltration events were reported after nine of the 12,156 rFVIII infusions were employed in the second and third generations, and administered to the cohort (0.074%), but none were defined chromatographic purification techniques were also performed) as serious. and furthermore the progressive removal of human and animal Of the 72 patients, 22 (30.5%) developed rFVIII inhibitors: proteins from the final formulation. The different generations a low titer (≤5 BU) was measured in 13 (59%) patients and of rFVIII products reflect the evolution of the methods used in a high titer (>5 BU) in 9 (40.9%) patients. In 12 of the 22 their manufacture. First-generation rFVIII production methods patients (54.5%), the inhibitors became undetectable, including include the use of animal proteins in the cell culture medium in 11 patients in the low-titer group. At the end of the study, nine and the addition of human serum albumin to stabilize the of the 72 patients (12.5%) still had a high titer of inhibitors. recombinant product; the culture medium of second-generation Ewenstein et al., in a prospective pharmacovigilance study that rFVIII contains human- or animal-derived proteins but not considered the incidence of inhibitor development worldwide human albumin; finally, the most recent, third-generation rFVIII in patients treated with Recombinate R , demonstrated that the products have no added human- or animal-derived proteins overall percentage was 11.9% (95% confidence interval [CI 5.05– at all. 28.0%]) for PUPs and 0.123% (CI: 0.030–0.512%) for PTPs. The For patients with severe HA, prophylaxis with FVIII incidence of high-titer inhibitors (>5 BU) was 5.96% (CI: 3.00– concentrates is the main treatment regimen to reduce joint 11.8%) for PUPs and 0.0554% (CI: 0.0113–0.271%) for PTPs (12). bleeding and other types of hemorrhage, thereby improving A trial comparing the PK of Recombinate R with that of the health-related quality of life (HRQoL) of both patients and pd-FVIII enrolled 69 PTPs with HA (67 with severe and two their caregivers (3, 4). Moreover, prophylaxis reduces inhibitor with moderate disease), who participated for a median of 3.7 formation, which is the major adverse event of hemophilia (1.0–5.7) years with the aim of comparing the PK of rFVIII treatment (5). with that of pd-FVIII. The safety and long-term home-treatment HA prophylaxis usually consists of intravenous FVIII efficacy of rFVIII was also assessed (13). At study entry, 44 injections every other day or three times per week due patients were HIV seropositive and 25 were seronegative. Three to the short half-life of FVIII of approximately 12 h (6). patients had a history of inhibitors, but not at study entry. The However, the need for frequent injections is a considerable results showed that the mean incremental recovery for rFVIII at burden for patients and their caregivers, particularly in baseline was 2.4%/IU/kg, essentially the same as that of pd-FVIII children and in those patients with poor venous access. The (2.5%/IU/kg). Furthermore, there was no significant change in development of EHL rFVIII products has slightly improved recovery over a 30-month period. The mean in vivo half-life of the management of these patients by allowing a reduction in rFVIII and pd-FVIII at baseline was the same: 14.7 h. However, the dose frequency, which in turn has increased adherence to over time, rFVIII demonstrated a statistically significant trend (p treatment (7). = 0.015) of a longer mean half-life, as determined at months 18 This review summarizes the characteristics of the rFVIII and 24 (Table 2). products currently available in Italy for the treatment of The Evaluation Study on Prophylaxis: a Randomized severe HA (Table 1). The potential clinical benefits of these Italian Trial (ESPRIT) compared prophylaxis with on-demand concentrates, as well as safety concerns including high titer treatment with the aim of preventing joint bleeding and joint inhibitor formation, are discussed. damage in children with severe HA (14). Forty of seventy-two
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TABLE 1 | Panel of recombinant factor VIII (rFVIII) products currently available in Italy.
Molecule Brand Protein structure Manufacturer/distributor Cellline
First-generation rFVIII Octocog Alfa Recombinate® Full-length rFVIII + Baxter/Bioviiix Chinese hamster albumin+pegylation ovary (CHO) Third-generation rFVIII Octocog alfa Advate® Full-length rFVIII; albumin-free Shire CHO Moroctocog Alfa ReFacto AF® BDD rFVIII; albumin-free Pfizer CHO Innovative third-generation rFVIII Octocog alfa Kovaltry® Full-length rFVIII (glycosylation sites, Bayer Baby hamster kidney sulfation of tyrosine sites) Turoctocog alfa NovoEight® BTD rFVIII NovoNordisk CHO (glycosylation sites, sulfation of tyrosine sites) Simoctocog Alfa Nuwiq® BDD rFVIII Octapharma/Kedrion Human embryonic kidney (HEK) Lonoctocog alfa Afstyla® Single-chain rFVIII CSL-Bhering CHO BDT-rFVIII Extended half-life rFVIII Efmoroctocog alfa Elocta® BDD rFVIII-Fc fusion Biogen Inc./Sobi HEK
TABLE 2 | Time course of the half-life of rFVIII (Recombinate®) and a comparison the on-demand group, developed inhibitors at 20 and 2 EDs. No with plasma-derived FVIII III (pdFVIII) [from (13)]. patient suffered from life- or limb-threatening bleeding or from hemorrhage that required hospitalization. Months n Half-life (h) Range P-value (mean ± SD) (vs. baseline)* Third-Generation Products Advate® pd-FVIII 61 14.7 ± 5.1 5.8–40.8 1 In 2003, a plasma/albumin-free formulation of octocog alfa rFVIII 65 14.7 ± 4.9 6.8–34.7 – containing sucrose was introduced as the first third-generation (Recombinate®) R baseline rFVIII originating from its precursor Recombinate . The 3 58 15.3 ± 50 5.6–30.6 0.52 adapted recombinant system used in the production of the rFVIII 6 62 15.3 ± 5.0 6.4–27.5 0.47 molecule includes culture medium free of human- or animal- 9 12 16.7 ± 7.7 10.8–34.7 0.25 derived additives. The CHO cell line co-expressing FL-FVIII 12 61 16.0 ± 8.7 8.1–60.2 0.32 and vWF has not undergone any further genetic manipulations, 15 11 16.9 ± 8.5 10.7–39.1 0.41 and the cDNA sequences encoding the recombinant proteins are identical to those used to obtain Recombinate R . Processing 18 55 18.4 ± 7.1 9.0–41.9 0.002 includes an S/D step, a viral inactivation that preserves the 21 4 14.5 ± 3.3 11.0–17.5 0.93 structural and functional integrity of the rFVIII molecule but 24 10 18.1 ± 4.2 10.9–25.8 0.04 inactivates lipid-enveloped infectious agents (15). Following the 27 3 15.7 ± 5.1 10.9–21.1 0.74 S/D step, the eluate is further purified using anion exchange 30 48 15.2 ± 4.9 7.5–28.7 0.59 chromatography. The newly introduced rFVIII, given the name R *p = 0.015 (Kruskal–Wallis test). Advate , contains the following stabilizers and excipients: mannitol, trehalose, sodium chloride, histidine, Tris, calcium chloride, polysorbate 80, and glutathione. eligible patients ranging in age from 1 to 7 years, completed The PK of Advate R has been evaluated in adults and children the study. Twenty were randomly assigned to be treated based on FVIII activity measurements in blood samples obtained prophylactically with Recombinate R at a dose of 25/IU kg three up to 48 h following each infusion. The mean half-life values times a week on nonconsecutive days and nineteen on-demand in adults and children differ as a function of patient age with the same product at a dose ≥25/IU kg. The results showed (Tables 3, 4). that children randomized to the prophylaxis regimen had Advate R has been evaluated in 11 clinical trials in PTPs and significantly fewer of all hemorrhagic events and joint bleeding in one trial in PUPs with severe to moderate HA (FVIII ≤2% of episodes than patients in the on-demand group (P < 0.05). Of normal). The five completed clinical trials have demonstrated the the five patients who developed inhibitors (12.5%), three were safety and efficacy of Advate R in adult and pediatric PTPs, for in the prophylaxis group and developed inhibitors after 24–48 both prophylactic and on-demand treatment regimens and for exposure days (EDs). The remaining two patients, who were in perioperative hemostatic coverage (Table 5)(17).
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A three-part study investigated the use of Advate R in 10- study (19). An integrated analysis of the safety and efficacy to 65-year-old PTPs without previous or detectable inhibitors. of Advate R examined the results of six previously conducted Fifty-six patients were randomized to Part 1 of the study, clinical prospective studies in a total of 234 patients with comparing the PK of Advate R with that of Recombinate R . HA (FVIII ≤ 2%) (median age 14.7 years; range: 0.02–72.7 Patients with severe or moderate HA (baseline FVIII ≤2%) years) and concluded that Advate R was safe and effective. One received an initial infusion (50 ± 5 IU/kg). Bioequivalence PTP developed an inhibitor, but there were no other safety between the older and newer products in terms of PK was concerns (20). demonstrated. Part 2 of the study evaluated the efficacy, safety, In a clinical trial that enrolled 55 PUPs (defined as having and immunogenicity of Advate R in 108 patients (baseline FVIII had up to three exposures to an FVIII product at the time ≤2%) who followed a standard fixed prophylactic regimen over of enrollment), 16 (29.1%) patients who received Advate R a period of at least 75 EDs. Of the 510 bleeding episodes that developed inhibitors: seven (12.7%) had high titers (>5 BU) and occurred during the study, 93% were resolved with 1–2 infusions nine (16.3%) had low titers. Inhibitors were detected at a median of Advate R , with an excellent/good hemostatic response rate of 13 EDs (min-max: 6–26 EDs) (16). of 86%. Part 3 was a double-blind, randomized, cross-over In all of the above-reported studies, no patient had to comparison of the PK of pilot-scale-prepared Advate R with withdraw from a clinical trial due to an adverse reaction. commercial-scale-prepared Advate R . The bioequivalence of the products was demonstrated (18). The long-term efficacy and ® safety of Advate R in PTPs with severe or moderate HA ReFacto AF R (baseline FVIII ≤2%) and no previous or detectable FVIII ReFacto AF (moroctocog alfa, Pfizer) is a bioequivalent inhibitors were shown in an open-label, two-part continuation albumin-free rFVIII produced from the second-generation R trial of patients who completed the pivotal phase III Advate R product ReFacto . It is manufactured using CHO cells grown in a chemically defined serum- and albumin-free cell culture medium that, per the definition of a third-generation product, contains no materials derived from human or animal sources. ReFacto AF differs from ReFacto R in that a synthetic peptide TABLE 3 | Studies of Advate ® [from (16)]. affinity ligand (TN8.2) replaces the murine monoclonal antibody Study patients Endpoints used in affinity chromatography and a 35-nm viral filtration step (n) is included in the purification process (21). Sucrose, calcium chloride dihydrate, L-histidine, sodium chloride, and polysorbate Pivotal (108) Pharmacokinetics, efficacy, safety, and 80 are added as excipients. immunogenicity in PTPs Two studies evaluated the properties of Refacto AF R in 204 Continuation* (82) Long-term pharmacokinetics, efficacy, safety, and immunogenicity in PTPs who completed PTPs with severe/moderate HA (22). The objectives of the studies the Pivotal study were similar: determinations of the PK equivalence of Refacto R R Surgery* (59) Efficacy and safety in PTPs undergoing AF vs FL-rFVIII (Advate -Baxter) and the efficacy and safety surgical/invasive procedures of Refacto AF R during surgery. These studies used standard Pediatric (53) Pharmacokinetics, efficacy, safety, and one-stage coagulation and chromogenic assays to measure FVIII immunogenicity in 6-year-old PTPs levels. The results showed that BDD-rFVIII PK was equivalent Japanese Pharmacokinetics, efficacy, safety, and to FL-rFVIII in 30 PTPs≥12 years of age (Table 5). In a cohort of Registry (15) immunogenicity in PTPs in Japan PUPs, the PK of Refacto AF R was evaluated using a chromogenic PTPs, previously treated patients. assay. In both PTPs and PUPs, the PK of the product included its *Patients were eligible to participate in more than one study. stability over long treatment times. Efficacy and safety were also
TABLE 4 | Pharmacokinetic parameters (mean ± SD) of ADVATE® by age group (data from product characteristics documentation).
Pharmacokinetic Mean ± SD (n = 7) Mean ± SD (n = 32) Mean ± SD (n = 24) Mean ± SD (n = 35) parameter (1 to <24 months) (2 to <5 years) (5 to <12 years) (12 to <16 years)
AUC0-t (IU*h/ml) 1,240 ± 330 1,164 ± 424 1,396 ± 506 1,300 ± 469 Incremental recovery at 2.1 ± 0.5 1.8 ± 0.4 2.1 ± 0.6 2.1 ± 0.5 Cmaxa (IU/dL per IU/kg) t ½ (h) 8.7 ± 1.4 9.5 ± 1.8 11.2 ± 3.5 12.0 ± 2.9 Maximum plasma 104 ± 27 91 ± 19 105 ± 34 103 ± 25 concentration post-infusion (IU/dL) Mean residence time (h) 10.4 ±2.5 11.8 ± 2.8 14.3 ± 4.3 14.9 ± 4.6 Volume of distribution at 0.4 ± 0.1 0.5 ± 0.1 0.6 ± 0.2 0.6 ± 0.1 steady state (dL/kg) Clearance (mL/kg*h) 4.3 ± 1.0 4.8 ± 1.5 4.1 ± 1.5 4.2 ± 1.2
Frontiers in Medicine | www.frontiersin.org 4 December 2019 | Volume 6 | Article 261 Schiavoni et al. Recombinant Factor VIII in Italy demonstrated both in the prophylactic use of Refacto AF R and immunogenicity of factor VIII products would require a much in on-demand treatment, including in patients with pre-existing larger sample. target joints. Moreover, in all nine patients treated with Refacto R AF for surgical support, hemostasis was achieved with minimal Kovaltry® blood loss (≤50 mL) and without the need for blood transfusions. Kovaltry R (octocog alfa, Bayer) is an unmodified Fl-rFVIII R Both studies confirmed the inhibitor safety of Refacto AF and with an amino acid sequence identical to that of sucrose- determined that the manufacturing modifications implemented formulated rFVIII (rFVIII-FS; Kogenate R FS, Bayer, Whippany, in the new BDD-rFVIII albumin-free cell culture process were NJ, USA) but developed using innovative techniques (26). not associated with neo-antigenicity. Kovaltry R and rFVIII-FS use the same cell expression More recently, the United Kingdom Haemophilia Centre system (baby hamster kidney [BHK] cells). The product Doctors’ Organization (UKHCDO) National Haemophilia includes the following excipients: 2.2% glycine, 1% sucrose, Database identified a consecutive cohort of 103 PUPs with 30 mM sodium chloride, 2.5 mM calcium chloride, 20 mM R severe HA treated with ReFacto AF (23). The study monitored histidine, and 80 ppm polysorbate 80. The production time to inhibitor development and associated risk factors. process incorporates two dedicated viral clearance steps: a Inhibitor development occurred in 35 patients (31.7%) prior detergent treatment step for inactivation and a 20-nm filtration to 50 EDs (P(t≤50) = 0.33, [95% CI: 0.25–0.43]), including 15 step to remove viruses and potential protein aggregates. (14.5%) with a high titer (≥5 BU; Pe(t≤50) = 0.16, [95% CI: Compared with rFVIII-FS, Kovaltry R has glycans shifted 0.10–0.25]). The incidence of inhibitors was comparable to that to higher branched structures and a somewhat higher in previously published studies of PUPs (24, 25). Anti-rFVIII degree of sialylation. These modifications were added to antibodies were significantly associated with both high-risk improve the product’s PK, specifically, giving it slower mutations and a family history of inhibitors. Anti-CHO clearance, a higher area under the curve (AUC) value, and antibodies were detected in a low percentage of patients but a longer half-life. were without a significant clinical effect. The authors concluded The PK of Kovaltry R was investigated in PTPs (0–61 years that, for the PUP cohort considered in the study, the proportion of age) with severe HA who were administered a dose of 50 developing inhibitors was similar to in previous PUP studies IU/kg (Table 6). Kovaltry R was also extensively studied in the R of ReFacto AF and comparable with PUP studies of other LEOPOLD clinical trials, comprising three open-label studies rFVIII concentrates; nevertheless, a formal comparison of the that enrolled patients of all age groups (children, adolescents, and adults) with severe HA. LEOPOLD I was a multi-center, open- label, cross-over, uncontrolled study conducted in adolescent and TABLE 5 | Pharmacokinetic study in PTPs treated with ReFacto AF® as adult PTPs (age ≥12 years to <65 years) to evaluate the efficacy, determined in a chromogenic assay (data from product characteristics safety, and PK of Kovaltry R in prophylaxis, and perioperative documentation). coverage. The prophylactic regimen (20–50 IU/kg two or three Pharmacokineticparameters Mean SD Median times per week) was assigned by the investigator based on the patient’s individual requirements. The annualized bleeding rate AUC0-t(IU*h/ml) 19.9 4.9 19.9 (ABR) was the primary efficacy endpoint (27). LEOPOLD II was t1/2(h) 14.8 5.6 12.7 a multi-center, open-label, cross-over, uncontrolled, randomized Clearance (ml/h kg) 2.4 0.75 2.3 study in adolescent and adult PTPs (age ≥12 years to <65 Mean residence time (h) 20.2 7.4 18.0 years) that evaluated the superiority of prophylaxis vs on-demand In vivo recovery (IU/dL/IU/kg) 2.4 0.38 2.5 treatment with Kovaltry R over a 1-year treatment period. The
TABLE 6 | Pharmacokinetic parameters for Kovaltry® (50 IU/kg dose) as determined in a chromogenic assay (data from product characteristics documentation).
Patient age
Pharmacokineticparameter 0to <6 years (n = 8) 6to <12 years (n = 10) 12–17years(n = 5) ≥18 years (n = 21)
AUC [IU h/dL] 1544.7 ± 387.1 1214.5 ± 395.1 1572.0 ± 448.0 2103.4 ± 702.8 Cmaxa [IU/dL] 89.6 ± 27.4 81.6± 17.8 132.5 ± 46.3 133.1 ± 20.4 t½ [h]b 12.1 ± 2.7 12.0 ± 2.1 14.4 ± 5.5 14.2 ± 3.5 MRT IVc [h] 17.7 ± 3.6 17.8 ± 2.9 19.8 ± 5.8 19.9 ± 4.9 Vssd [dL/kg] 0.57 ± 0.13 0.79 ± 0.23 0.71 ± 0.39 0.50 ± 0.11 Clearance [dL/h/kg] 0.033 ± 0.009 0.045 ± 0.016 0.034 ± 0.010 0.027 ± 0.010
AUC, area under the curve. aMaximum drug concentration in plasma after a single dose. bTerminal half-life. cMean residence time after i.v. administration. dApparent volume distribution at steady state.
Frontiers in Medicine | www.frontiersin.org 5 December 2019 | Volume 6 | Article 261 Schiavoni et al. Recombinant Factor VIII in Italy prophylactic regimen was 20–30 IU/kg two times per week or was achieved in all surgical interventions, and no failure 30–40 IU/kg three times per week. The treatment group was was reported. assigned by randomization. The primary efficacy endpoint was The efficacy and safety of turoctocog alfa were evaluated in ABR (28). the guardian 1 trial (31). Its primary objective was to evaluate LEOPOLD KIDS (part A) was a multi-center, open- safety in adolescent and adult PTPs with severe HA, especially the label, uncontrolled study of Kovaltry R in pediatric PTPs incidence of FVIII inhibitor development. Other endpoints were (age ≤12 years; ≥50 EDs). The PK, efficacy, and safety of efficacy during bleeding episode treatment, bleeding control, and routine prophylaxis and the perioperative management of ABR. The study concluded that turoctocog alfa was safe and bleeding were investigated. The primary efficacy variable was well-tolerated in adolescent and adult patients with HA. the ABR that occurred during routine prophylaxis within A multicenter, multinational, open-label, sequential dosing 48 h of the previous infusion. ABR during prophylaxis, PK study comparing turoctocog alfa with Advate R was independent of the time of infusion, was also analyzed. The conducted in 23 patients with severe HA (32). The results of prophylactic regimen was 25–50 IU/kg at frequencies of either the primary PK were comparable between the two products. The two times per week, three times per week or every other 90% CI for the treatment ratio of Advate R to turoctocog alfa was day, adapted to the patient’s need by the investigator. In within the acceptable bioequivalence interval of 0.8–1.25. LEOPOLD KIDS part A, Kovaltry R values for the maximum Guardian 3 evaluated the safety and efficacy of turoctocog concentration and AUC tended to be lower in children than alfa in pediatric patients 0–11 years of age with severe HA in adults. LEOPOLD-KIDS part B, a study in PUPs, is (FVIII <1%). Patients with >50 EDs to any FVIII product were ongoing (29). included in the study (33). The primary objective and all of In all of the completed LEOPOLD studies, Kovaltry R the efficacy endpoints were identical to those in guardian 1. was shown to be efficacious, whether for prophylaxis, on- No patients developed FVIII inhibitors during the study. Three demand treatment, or perioperative hemostasis. The effective serious adverse events occurred that were not related to the study prophylactic dose, defined as achieving a low ABR, was 20– medication: soft-tissue injury, viral gastroenteritis, and device- 40 IU/kg, given two or three times per week. The incidence of related infections. Overall, the authors concluded that turoctocog treatment-related adverse events was <7% across all LEOPOLD alfa is safe and well-tolerated in pediatric patients with HA. studies, and no PTPs developed inhibitors during the completed A secondary endpoint in the guardian 1 and 3 studies was primary studies (30). HRQoL related to the use of turoctocog alfa. Those results showed a fairly stable HRQoL for patients already treated with prophylaxis (34). The greatest improvement in HRQoL was NovoEight® seen in patients who switched from on-demand therapy to NovoEight R (turoctocog alfa, Novo Nordisk) is produced from prophylaxis. Of the 13 surgeries (10 major, 3 minor) assessed CHO cell lines without the use of human or animal plasma. throughout the guardian 1 and 3 studies, the hemostatic response Turoctocog alfa includes two amino acid chains, a heavy chain achieved with turoctocog alfa was reported as excellent or good in and a light chain, joined by non-covalent bonds. This activated all of them. glycoprotein has the same molecular structure as human FVIII All patients in the guardian 1 and 3 studies or in phase 1 and is subjected to post-translational changes that are similar to PK trials were eligible for participation in the extension study, those of the plasma-derived molecule. The Tyr1680 (total native guardian 2, which assessed the efficacy and safety of turoctocog length) sulfation site, important for vWF binding, is fully sulfated alfa in prophylaxis or on-demand treatment in PTPs of all in the turoctocog alfa molecule. The high affinity with vWF ages. The primary safety endpoint was the frequency of FVIII helps to reduce the renal clearance of the product and prolong inhibitor development. Efficacy endpoints included ABR during its half-life. Sucrose, sodium chloride, L-histidine, polysorbate prophylaxis, hemostatic response in the treatment of bleeds, and 80, L-methionine, calcium chloride dihydrate, sodium hydroxide, the number of injections required to treat bleeds. The results and hydrochloric acid are the excipients. Viral inactivation showed that the extended use of turoctocog alfa was safe and is ensured by detergent inactivation and a 20-nm nano- effective in the prevention and treatment of bleeding episodes in filtration step. patients of all ages (35). Three multicenter, open-label, uncontrolled studies were The clinical trial GUARDIANTM 4 will assess the efficacy conducted to evaluate the safety and efficacy of turoctocog and safety of turoctocog alfa in the prevention and treatment alfa in the prevention and treatment of bleeding in PTPs with of bleeds in treatment-naïve HA patients (36). GUARDIANTM severe HA (FVIII ≤1%). The studies included 213 patients: 5 is assessing the safety and efficacy of turoctocog alfa in the 150 adolescent and adult patients >12 years of age without long-term prevention and treatment of bleeding episodes. The inhibitors and with ≥150 EDs, and 63 pediatric patients PK parameters of turoctocog alfa in patients with severe HA are <12 years of age without inhibitors and with ≥50 EDs. Of reported in Table 7. these 213 patients, 187 participated in the extension safety study. Treatment with turoctocog alfa was shown to be safe Nuwiq® and effective for bleeding treatment and for prophylaxis in Simoctocog alfa (Nuwiq R , Octapharma-Kedrion) is a BDD- 14 patients undergoing a total of 14 surgical interventions, rFVIII produced in genetically modified human embryonic including 13 major and 1 minor operation; hemostasis kidney cells, rhFVIII, and so is defined as a fourth-generation
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TABLE 7 | Pharmacokinetic profile of Turoctocog Alfa in PTPs with severe HA (coagulation assay) (data from product characteristics documentation).
Patient age
PKparameters 0to <6 years (n = 14) 6to <12 years (n = 14) ≥12 years (n = 33)
In vivo recovery (IU/ml)/(IU/kg) 0.018 (0.007) 0.020 (0.004) 0.022 (0.004) AUC (UI*h)/ml) 9.92(4.11) 11.09(3.74) 15.26(5.77) Clearance (ml/h/kg) 6.21(3.66) 5.02(1.68) 3.63(1.09) t ½ (h) 7.65(1.84) 8.02(1.89) 11.00(4.65) Vss (ml/kg) 56.68(26.43) 46.82(10.63) 47.40(9.21) Cmax (IU/ml) 1.00(0.58) 1.07(0.35) 1.226(0.41)
Mean values are reported. Cmax, maximum drug concentration in plasma after a single dose; VSS, apparent volume distribution at steady state. rFVIII product (37, 38). It consists of a heavy chain followed CI: 1.5–3.4) over on-demand treatment (ABR 57.7; CI: 43.3–76.9) by a 16-amino acid linker sequence and a light chain. was shown. The molecule is produced with human post-translational Prospective non-registrative trials, such as the extension modifications but without human- or animal-derived materials studies GENA-11 (extension of GENA-01) and GENA- being added to the serum medium. Because of its specific post- 13 (extension of GENA-03) and the new study GENA-09 translational modifications, a decreased immunogenicity has and its extension GENA-04, have also been carried out been hypothesized. The excipients are sucrose, sodium chloride, (43). The PK profiles of simoctocog alfa with respect to calcium chloride bihydrate, arginine hydrochloride, sodium prophylaxis, breakthrough bleeding, and surgical prophylaxis citrate bihydrate, and poloxamer 188. The purification process were investigated in 22 PTPs in a single center in Russia. comprises five chromatographic steps, S/D treatment, and 20-nm GENA-21 (NuPreviq), a prospective, multicenter, open-label, nanofiltration in order to minimize the risk of pathogens in the phase III study evaluating PK-guided prophylaxis vs on-demand final product. treatment with simoctocog alfa in 66 adult PTPs with severe Three studies (GENA 01, GENA 08, and GENA-03) were HA, was recently completed. Personalized prophylaxis with carried out in 135 PTPs ≥12 years (74 adult and 61 pediatric simoctocog alfa was shown to be a more convenient treatment patients) with severe HA treated with simoctocog alfa for in the 58% of patients who were able to extend the injection bleeding episodes or the prevention of bleeding during surgery intervals from three times weekly to twice weekly or less. In (39, 40). In the 22 patients included in GENA-01, 91% of addition to less factor consumption, a lower ABR was recorded the 986 recorded bleeding episodes were resolved with one in this group (44). intravenous infusion of concentrate. Replacement therapy with To assess the efficacy of simoctocog alfa with respect to simoctocog alfa was rated as excellent or good for 94% of the surgical prophylaxis, an integrated analysis of five studies bleeding episodes. Hemostasis achieved with the preparate in (GENA-01, GENA-03, GENA-04, GENA-08, and GENA-09) was the two surgeries that occurred during the study was also rated carried out due to the limited number of PTPs enrolled in each as excellent. study. Overall, 19 patients underwent 34 surgical procedures (20 GENA 08 evaluated 32 patients age ≥18 years who were placed minor and 14 major). Drug efficacy was rated as excellent or good on standard prophylaxis with simoctocog alfa for the prevention in 100% of the minor and 92% of the major operations. None of or treatment of hemorrhagic events. Hemostatic prophylaxis the patients developed inhibitors. during surgery was also determined (41). In patients receiving Finally, the GENA-05 (NuProtect) trial evaluated the the product prophylactically, an average of 0.19 bleeds per month immunogenicity, safety, and efficacy of simoctocog alfa in PUPs were recorded for each patient. Treatment with the concentrate with severe HA (45). Data from a preplanned interim analysis was rated as excellent or good based on the control of the majority were analyzed for 66 PUPs with ≥20 EDs. The authors reported of episodes (81.5%). Almost all hemorrhages were resolved witha that 8 of the patients developed inhibitors after a median of single injection. In the five surgeries carried out during the study, 11.5 EDs (range 6–24); low-titer inhibitors were observed in 5 the drug was rated as excellent in preventing bleeding during four patients (4 transient). The cumulative incidence (CI) was 12.8% of the operations and moderately efficacious in one. (4.5–21.2%) for high-titer inhibitors and 20.8% (10.7–31.0%) for GENA-03 evaluated the efficacy of simoctocog alfa in the all inhibitors. The median value of ABR was 0 for spontaneous treatment of bleeding episodes in 59 children 2–12 years of age. bleeds and 2.40 for all other bleeding in the inhibitor-free period. Resolution in 81% of the bleeding episodes was achieved with one Simoctocog alfa turned out to be effective, being excellent or or two injections (42). The efficacy of prophylaxis vs on-demand good in treating 91.8% of the hemorrhagic episodes, and was treatment with simoctocog alfa in previously treated adults with also effective in surgical prophylaxis, being excellent or good for severe HA was investigated in an indirect analysis comparing eight (89%) interventions and moderate for one (11%). No side the results of the GENA-01 (on-demand arm) and GENA-08 effects or adverse reactions were reported (46). However, the PK (prophylaxis arm) trials. The superiority of prophylaxis (ABR 2.3; of simoctocog alfa, in particular its half-life, was generally not
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TABLE 8 | Pharmacokinetic profile of Simoctocog Alfa (dose: 50 IU/Kg) in TABLE 9 | Pharmacokinetic parameters in children, adolescents, and adults by pediatric, adolescent, and adult PTPs with severe HA (chromogenic substrate age category following a single i.v. injection of 50 IU/kg of lonoctocog alfa assay) (data from product characteristics documentation). (chromogenic assay) (data from product characteristics documentation).
Patient age Patient age
Pharmacokinetic 2–5 years 6–12 years 18–65 years Pharmacokinetic 0 to <6 ≥6 to <12 ≥12 to <18 ≥18 years parameter (n = 13) (n = 12) (n = 20) parameter years years years (n = 81) (n = 20) (n = 19) (n = 10) AUC (h*UI/ml) 11.7 ± 5.3 13.2 ± 3.4 22.6 ± 8.0 t 1/2 (h) 9.5 ± 3.3 10.0 ± 1.9 14.7 ± 10.4 IR (IU/dL)/(IU/kg) 1.60 (21.1) 1.66 (19.7) 2.00 (20.8) 1.69 (24.8) IVR (%/UI/kg) 1.9 ± 0.3 1.9 ± 0.4 2.5 ± 0.4 Cmax(IU/dL) 80.2(20.6) 83.5(19.5) 106(18.1) 89.7(24.8) Clearance (ml/h/kg) 5.4 ± 2.4 4.3 ± 1,2 3.0 ± 1.2 AUC0-inf(IU*h/dL) 1,080(31.0) 1,170(26.3) 1,960(33.1) 1,540 (36.5) t1/2(h) 10.4(28.7) 10.2(19.4) 14.2(26.0) 14.3(33.3) Values reported are mean ± SD. Mean residence time 12.4(25.0) 12.3(16.8) 20.4(25.8) 20.0(32.2) (h) Clearance (mL/h/kg) 5.07 (29.6) 4.63 (29.5) 2.90 (34.4) 3.80 (46.9) superior to those of third-generation rFVIII concentrates. The Vss(mL/kg) 71.0(11.8) 67.1(22.3) 55.2(20.8) 68.5(29.9) PK of simoctocog alfa is reported in Table 8. Values are reported as the arithmetic mean, coefficient of variation [%]. IR, incremental recovery; Cmax, maximum drug concentration in plasma after a single ® Afstyla dose; VSS, apparent volume distribution at steady state. Lonoctocog Alfa (Afstyla R , CSL Behring) is a unique, single- chain rVIII molecule. It has a truncated B-domain and heavy and light chains covalently linked to form a stable and homogeneous ABR of 1.14 (Q1, Q3: 0.0, 4.2) and a median of spontaneous compound. The molecule binds with high affinity to vWF, which ABR of 0.00 (Q1, Q3: 0.0, 2.4) were recorded. The hemostatic results in its increased stability and protection from degradation. efficacy was good or excellent based on a 93.8% control rate Lonoctocog alfa is produced by recombinant DNA technology for bleeding episodes. The 13 patients who underwent 16 in CHO cells. L-histidine, calcium chloride, sodium chloride, surgical procedures were given lonoctocog alfa for hemostatic sucrose, and polysorbate 80 are the excipients. Safety from prophylaxis. In the sub-analysis of perioperative management, infective agents is ensured by chromatography, S/D treatment, the efficacy of lonoctocog alfa was rated as excellent or good and serial nanofiltration. in 100% of the procedures. Data on inhibitor incidence in Lonoctocog alfa was shown to be effective for prophylaxis, PUPs participating in the ongoing CSL627 UNDERSCORE 3001 treatment, and the surgical management of bleeding episodes extension study are awaited. in PTPs with severe HA. Two prospective, non-comparative, multicenter trials (AFFINITY program) were carried out, one EHL rFVIII in children and the other in adolescents/adults. Eligible patients Elocta® had been treated with an FVIII product for 50–150 EDs. The Efmoroctocog alfa (Elocta R , Sobi-Biogen) is a first-in-class co-primary efficacy endpoints were the treatment success rate fusion protein consisting of a single molecule of human (excellent or good) and ABR in routine prophylaxis, which were BDD-rFVIII covalently linked to the dimeric Fc domain of compared with on-demand treatment (47). The three-part study human immunoglobulin G1 (rFVIII-Fc). The excipients used included adolescent/adult patients ≥12–65 years of age. Part are sucrose, sodium chloride, L-histidine, calcium chloride 1 evaluated the PK and short-term safety of a single dose of dihydrate, and polysorbate 20. The half-life of efmoroctocog alfa lonoctocog alfa. Patients who completed Part 1 participated in is about 1.5 times longer than that of conventional pd-FVIII and Part 2, which compared prophylaxis with on-demand treatment. of rFVIII products. Part 3 included 173 other PTPs, 146 of whom were treated on The efficacy of efmoroctocog alfa in prophylaxis, treatment prophylaxis three times per week. of acute hemorrhage, and perioperative management has been In the Part 1 study on 27 PTPs, the half-life of lonoctocog investigated in two open-label, non-comparative, multinational alfa was slightly longer (14.5 ± 3.8 vs. 13.3 ± 4.4h) than that phase III trials enrolling PTPs ≥12 (A-LONG) or <12 (Kids A- of Recombinate R , and clearance was 28–31% lower. In a post- LONG) years of age who had severe HA. Adults and adolescents hoc sub-analysis, the vWF antigen level for both products was were eligible for A-LONG if they had been treated with any FVIII shown to have a positive effect on half-life and a negative effect product for ≥150 EDs and had a history of ≥12 bleeding events in on clearance. This finding suggests that stronger binding to the 12 months prior to the study. Children were eligible to enter vWF improves the PK profile of FVIII concentrates. In pediatric Kids A-LONG if they had been treated with any FVIII product PTPs, the half-life was shorter and the clearance longer than in for ≥50 EDs (50). adolescents and adults (48)(Table 9). The A-LONG and Kids A-LONG studies demonstrated the In Parts 2 and 3, the adult/adolescent patients were assigned EHL of efmoroctocog alfa (1.4- to 1.8-fold longer than that of to different prophylaxis regimens or on-demand therapy (20– Recombinate R ). These pivotal phase III trials also showed that 40 IU/kg every second day or 20–50 IU/kg two to three times the routine prophylactic administration of efmoroctocog alfa in per week) (47, 49). In all prophylactic regimens, a low median PTPs (1–2 times per week in adults/adolescents ≥12 years of age;
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twice-weekly in children <12 years of age) was well tolerated, TABLE 10 | Pharmacokinetic profile of efmoroctocog alfa (coagulation and with no evidence of increased immunogenicity. In addition, chromogenic assays) (data from product characteristics documentation). efmoroctocog alfa was effective in preventing bleeding episodes, Pharmacokinetic ELOCTAa ELOCTAb including in target joints. Prophylaxis with efmoroctocog alfa parameters (n = 28) (n = 27) was also associated with maintained or increased physical activity in the majority of patients, including those with target joints AUC/dose 51.2 47.5 at baseline. Recommended long-term prophylaxis consists of (UI*h/dL per UI/kg) (45.0–58.4) (41.6–54.2) intravenous injections of efmoroctocog alfa every 3–5 days (51). Cmax (UI/dL) 108 131 The ASPIRE extension study was completed in 2018. The (101–115) (104–165) final results demonstrated the safety and sustained efficacy Clearance 1.95 2.11 of efmoroctocog alfa for up to 4 years in PTPs with severe (mL/h/kg) (1.71–2.22) (1.85–2.41) HA. Data from the study also showed the safety and efficacy t½ (h) 19.0 20.9 (17.0–21.1) (18.2–23.9) of efmoroctocog alfa in the parent trials with respect to the prevention and treatment of bleeding events, including in the Mean residence 25.2 25.0 time (h) (22.7–27.9) (22.4–27.8) surgical setting (52). No inhibitors, treatment-related serious Vss (mL/kg) 49.1 52.6 adverse events or deaths were reported. The ABR remained (46.6–51.7) (47.4–58.3) low: with individualized rFVIII-Fc prophylaxis, the median spontaneous ABR across all of the studied age groups was <1 and Values are reported together with their 95% confidence intervals. VSS, apparent volume distribution at steady state. the median spontaneous joint ABR was 0. Improved joint-health aCoagulation assay. scores demonstrated a clinical benefit beyond the low bleeding bChromogenic assay. rates. Both A-LONG and Kids A-LONG exclusively enrolled PTPs with severe HA. Since the cumulative risk of inhibitor development is higher in PUPs than in PTPs (∼30 % vs. 2–3 per been subjected to virus inactivation or removal treatments, the 1,000 patient-years), an open-label, multicenter, single-arm phase manufacturers of those products introduced virus sterilization III study (PUPs A-LONG) is evaluating the safety and efficacy of steps into their production methods and increased the purity efmoroctocog alfa in the prevention and treatment of bleeding of the preparations via DNA genetic engineering, thus greatly episodes in PUPs <6 years of age who have severe HA. The improving safety. All of the rFVIII products currently available primary endpoint is the development of inhibitors; secondary in Italy have been tested in well-conducted clinical trials in which objectives are efficacy, factor consumption, and experience with they were shown to be effective and safe. However, the ever- immune tolerance induction in participants with inhibitors (53). increasing purity of the molecule has made these preparations Although susceptible to over- or under-estimation, an interim more susceptible to inhibitor development than was the case analysis of A-LONG PUPs is currently available in anticipation with pd-FVIII concentrates. Consequently, there is currently an of the final data. Among the 95 enrolled PUPs, 89 received the urgent need to minimize the risk of inhibitor development linked studied treatment, of whom 20 were started on a prophylactic to replacement treatment/prophylaxis with rFVIII products. This regimen and 69 on an episodic regimen. Among the latter, 50 is especially the case for high-titer inhibitors, which, according to patients were switched to prophylaxis, such that the prophylactic clinical studies carried out worldwide, mainly develop in PUPs arm of the study consisted of 72 pediatric patients. The pre- after ≥ 25/50 EDs. planned PUP-A interim analysis, based on a data cut-off of 12 The first-generation rFVIII molecules Recombinate R and March 2018, showed that the study enrolled a high proportion Kogenate R were introduced in Italy in the 1990s. Recombinate R of patients with a family history of inhibitors (20%), a known is currently distributed in Italy by BIOVIIIx. The characteristic of risk factor for inhibitor development. According to the primary the product that accounts for its continued use is its stabilization analysis (68 patients with ≥10 EDs), inhibitors occurred in 30.9% by human serum albumin and polyethylene glycol (PEG 3350). of patients (n = 21); the rate of high-titer inhibitors was 14.7% (n The covalent linkage of polyethylene glycol (PEGylation) to = 10). High-titer inhibitors developed after up to 11 EDs (median FVIII increases the molecular weight and size of the protein 8; range 4–11) (54, 55). Efmoroctocog alfa prophylaxis was well- by surrounding it with a hydrophilic cloud. This molecular tolerated and efficacious, with an overall median ABR of 1.16 (0, change is thought to have a protective effect, reducing the 4.14) and no spontaneous joint bleeding. The PK profile of the product’s susceptibility to proteolytic activity and degradation. product is reported in Table 10. PEGylation also changes the surface charge of the protein, Data on inhibitor frequency in PTPs and PUPs using all of the which may interfere with its clearance, as the half-life of rFVIII products are reported in Table 11. PEGylated rFVIII is longer than that of non-PEGylated FL- rFVIII (56). In addition, co-transfection of rvWF with the rFVIII- encoding plasmid during the initial production process not DISCUSSION only helps to stabilize Recombinate R but may also protect it from inhibitor development. The putative modulatory role of Following the outbreak in the 1980s of blood-borne infectious vWF in the development of inhibitors in patients with HA is diseases (particularly HIV and HBV/HCV infections) in being intensely investigated, and differences in immunogenicity hemophilia patients who received pd-FVIII products that had not between pd-FVIII and rFVIII concentrates have been attributed
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TABLE 11 | Rate of total and high-titer inhibitors in PTPs and PUPs using rFVIII products in Italy.
Recombinant product Total incidence Incidence of Total incidence of Incidence of high-titer of inhibitors in high-titer inhibitors in PUPs (%) inhibitors in PUPs (%) PTPs (%) inhibitors in PTPs (%)
Recombinate® (Baxter-Bioviiix): first-generation 0.123a 0.55 30.5a 12.9 full-length rFVIII ReFacto AF® (Pfizer): third-generation BDD-rFVIII – – 33 14.5 Advate AF® (Bayer): third generation full-length rFVIII – – 29.1 12.7 Kovaltry® (Bayer): third-generation full-length rFVIII 0 0 Ongoing Ongoing LEOPOLD KIDs (Part B) LEOPOLD KIDs (Part B) study study Novoeight® (Novo Nordisk): third-generation BDT 0 0 Ongoing guardian 4 Ongoing guardian 4 rFVIII study study Nuwiq® (Octapharma-Kedrion): third-generation 0 0 20.8 12.8 BDD-rFVIII Afstyla® (CSL Behring): third-generation single-chain 0 0 Ongoing Ongoing rFVIII CSL627 UNDERSCORE CSL627 UNDERSCORE 3001 3001 extension study extension study Elocta® (Biogen-Sobi): extended half-life BDD- rFVIIIb 0 0 30.9 14.7b rFVIII, recombinant factor VIII; BDD, B-domain-deleted; PUPs, previously untreated patients; PTPs, previously treated patients. aIncluding high titer, low titer, and transient inhibitors. bInterim analysis of A LONG study PUPs. to vWF (57–61). These considerations may explain the trend developed in PTPs. Anti-HSP70 antibodies were detected in some of Recombinate R to show a longer half-life over time (Table 2) patients but were without any clinical effect. and a similar or lower rate of high-titer inhibitors in PUPs Turoctocog alfa-rFVIII (Novoeight R ) was the first BDT- (11, 62) (Table 11). Moreover, the absence of polysorbate 80 rFVIII. Its high affinity for vWF accounts for its slightly longer in the concentrate improves the safety of the product (63). In half-life. The guardian study of a large population of PTPs PUPs and PTPs treated with Recombinate R over many decades, with severe HA demonstrated that turoctocog alfa is effective there have been no adverse reactions or side effects attributable and safe in preventing and treating bleeding, is well tolerated, to continuous exposure to the excipient PEG, despite a study and is not associated with unexpected safety issues or FVIII showing its potential accumulation or damage (e.g., vacuolation inhibitor development. A PK study comparing turoctocog alfa in epithelial cells of the choroid plexus) in tissues (64). with Advate R showed that the primary PK parameters of the two Advate R (octocog alfa), a third-generation, human-protein- products were comparable. free FL-rFVIII, is derived from Recombinate R and has similar Of particular interest is the BDD-rFVIII simoctocog efficacy, safety, and immunogenicity in PTPs and PUPs with alfa (Nuwiq R ), the first product obtained from a human severe HA. However, Advate R and other rFVIII products embryonic kidney cell line. The GENA study and its extensions differ from Recombinate R in that their excipients include demonstrated that simoctocog alfa was a good/excellent rFVIII polysorbate 80. in adult and pediatric PTPs, whether for prophylaxis, on-demand The BDD-rFVIII ReFacto AF R is an innovative structural treatment, or intraoperative bleeding prevention. Definitive data modification of FVIII derived from ReFacto R . Its efficacy is on inhibitor development in a large population of PTPs enrolled equivalent to that of FL-rFVIII products. The immunogenicity in various prospective trials, as well as preliminary data from the of ReFacto AF R in PUPs was evaluated in a study conducted NuProtect study in PUPs, suggest a low inhibitor rate in patients by UKHCDO. The results showed a slightly high incidence of treated with simoctocog alfa. high-titer inhibitors (14.5%) in PUPs. Lonoctocog alfa (Afstyla R ) is a unique single-chain Kovaltry R , a derivative of Kogenate FS R , is an unmodified rFVIII. Its safety, efficacy, and PK profile were evaluated FL-rFVIII produced using a genetically engineered BHK cell in two open-label studies, one in children and the other in line. Its post-translational modifications are similar to those adolescents/adult populations. The results of those studies of endogenous FVIII, including glycosylation and tyrosine showed good/excellent hemostatic efficacy both in the control sulfation, which account for the high affinity of Kogenate FS R for of episodic hemorrhagic events and in bleeding prophylaxis. In vWF, in turn slightly prolonging its half-life. The results from the addition, the adolescent/adults study demonstrated hemostatic Leopold study confirmed the efficacy and safety of Kovaltry R for efficacy during the perioperative management of bleeding in twice/thrice weekly prophylaxis, on-demand treatment, and the patients undergoing surgical procedures. The high affinity of control of perioperative bleeding in patients of all ages. Moreover, lonoctocog alfa for vWF results in its stabilization and reduced at least within the completed primary studies, no FVIII inhibitors clearance of rFVIII molecules. Data on inhibitor incidence in
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PUPs from the ongoing CSL627 UNDERSCORE 3001 extension CONCLUSION study are not yet available. Efmoroctocog alfa (Elocta R ), a BDD-human r-FVIII Currently, the National Health Care System in Italy guarantees covalently linked to the Fc domain of human IgG1, is the only the availability of rFVIII products for the prophylaxis and EHL rFVIII commercially available in Italy. The half-life of episodic treatment of patients with severe HA. Third-generation efmoroctocog alfa is 1.5–1.8 times longer than that of other, rFVIII concentrates represent a wide range of high-quality conventional rFVIII products (19 h and 12–14 h in patients ages products that offer efficacy and safety in all therapeutic regimens. ≥12 and <12 years, respectively). Data from pivotal phase III Today, with the availability of EHL-rFVIII, the quality of life studies (A-LONG in adults and adolescents ≥12 years of age; of both patients and caregivers is improving. Nonetheless, R Kids A-LONG in children <12 years of age) and an extension the first-generation rFVIII Recombinate , far from being study (ASPIRE) demonstrated the long-term effectiveness of obsolete, continues to be effective and safe. The development efmoroctocog alfa for the treatment of acute bleeding episodes, of inhibitors, the most serious complication of replacement perioperative management and routine prophylaxis in PTPs with therapy, seems to be of very limited importance in PTPs severe HA. who have switched to third-generation rFVIII products. In Routine prophylaxis consisting of intravenous injections every clinical studies, all of these newly developed concentrates 3–5 days is recommended, although once weekly may be suitable have demonstrated efficacy and safety; nevertheless, they for some patients. Neither inhibitor development nor severe do not seem to be less immunogenic in PUPs than other adverse events have been reported. Preliminary data from an rFVIII products. Despite the structural and functional interim analysis of the PUPs A-LONG ongoing study now improvements of new rFVIII concentrates, the incidence of available would confirm the hemostatic efficacy of efmoroctocog high-titer inhibitors in PUPs remains a very significant and still alfa. The cumulative incidence of inhibitor development is unsolved problem. 30.9% while the rate of high-titer inhibitor development is 14.7%. Efmoroctocog alfa used prophylactically is well-tolerated AUTHOR CONTRIBUTIONS and efficacious, with a very low median ABR overall and no spontaneous joint bleeding. All authors wrote and revised the final version of the manuscript.
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